In the context of mitigating greenhouse gas (GHG) and other emissions in the heavy-duty transportation sector, hydrogen (H2) has emerged as a prominent candidate and a viable substitute for hydrocarbon fuels. Hydrogen internal combustion engines (H2-ICEs) have been demonstrated as one of the most cost-effective solutions for decarbonizing heavy-duty transport. Nonetheless, given the transport and combustion properties of this fuel, specific design considerations are required for efficient and robust energy conversion process in the engine. Therefore, this work involved developing and optimizing the combustion system of a 6-cylinder 15L H2 directinjection spark-ignited (DISI) engine through simulation methodologies. A comprehensive computational fluid dynamics (CFD) analysis was conducted to evaluate the impact of gaseous fuel spray forming caps, fuel injection strategies, in-cylinder swirl motion, and spark timing on mixture formation, engine combustion performance, and emission control. The investigation reveals that nozzle cap designs play a crucial role in influencing mixing performance. Singlehole cap exhibited poor mixing, while multi-hole caps initially enhanced homogeneity. However, reaching a critical threshold, plume-to-plume collapse prevented mixing optimization. These factors subsequently impacted engine efficiency and the formation of NOx emissions. The start of injection (SOI) timing was found have an important effect on mixing performance. Specific SOI timings, particularly in proximity to intake valve closure (IVC), are identified as effective strategies for enhancing mixture homogeneity. Moreover, the study demonstrates that excessive swirl ratios lead to heightened NOx emissions due to the formation of locally rich mixtures, whereas moderate swirl ratios effectively mitigate emissions. Furthermore, simulation-based analysis allowed for the generation of an ideal mixing scenario, highlighting the importance of optimal mixing to avoid potential abnormal combustion and excessive emissions. Overly advanced ignition timing could induce auto-ignition, resulting in reduced indicated thermal efficiency (ITE), increased maximum pressure rise rate (MPRR), and higher NOx emissions. These findings represent significant progress in the development of hydrogen engine technology, offering tangible pathways toward achieving both environmental sustainability and technological advancement in heavy-duty transportation.